Cyclodextrins (CDs) are cyclic molecules formed by (1,4)-linked α-D(+)-glucopyranoside units (FIG. 1C). The most common types are α-, β-, and γ-CDs, comprising 6, 7 and 8 α-D(+)-glucopyranoside units, respectively (FIG. 1A). As shown in FIG. 1B, CD molecules have the shapes like truncated cones with the primary hydroxyl groups at the narrow edges and secondary hydroxyl groups at the wider edges. The inner cavities of CDs are more hydrophobic and outer peripheries are more hydrophilic. In an aqueous environment, apolar molecules or apolar sections of molecules can be extracted from water into the CDs' cavities to form inclusion complexes (ICs) if the sizes of the molecules fit the cavities of the CDs. The driving force for the formation of the ICs is primarily due to hydrophobic effect. Owing to this property, CDs have been used in many industrial applications including pharmaceuticals and industrial fields including foods, cosmetics and textiles as solubilizing agents, stabilizers, emulsifiers, etc.
Unlike acyclic saccharides, the solubilities of CDs in water are not great because intramolecular hydrogen bonds can form between the (OH)2 groups and the (OH)3 groups along the peripheral edges, which limits their hydrogen bonding interactions with water. In the β-CD molecule, a complete secondary belt is formed by these hydrogen bonds, which makes β-CD rather rigid and less soluble in water than α-CD and γ-CD. The solubilities and other physical properties of CDs are given in Table 1.
TABLE 1Physical properties of CDsα-CDβ-CDγ-CDNumber of glucopyranoside units678Molecular weight (MW) (g/mol)97211351297Solubility in water (g/100 mL)14.51.8523.2Melting point (° C.)275280275
CDs with molecular weights from 1000 Da to 2000 Da are not significantly absorbed from the gastrointestinal tract. α-CD, β-CD, and γ-CD are not hydrolyzed by human salivary and pancreatic amylases, although α-CD and β-CD can be fermented in the intestinal microflora. Because of their inertness and low tissue penetration, CDs are considered as safe expedients for oral drug delivery applications.
Among all the CDs, β-CD is the most favored one in drug delivery applications. However, unmodified β-CD cannot be so safely applied for parenteral administration because its low water solubility can cause adverse effects (e.g., nephrotoxicity, given that CDs are mainly excreted unchanged in urine). To minimize the potential side effects and improve the water solubility of β-CD, many chemically modified β-CDs have been synthesized by substituting the hydroxyl groups with various other functional groups. The strategy of these substitutions is to introduce other functional groups to break down the intramolecular hydrogen bonds of β-CD. So far, several β-CD derivatives have been produced for pharmaceutical applications, including methylated β-CDs, 2-hydroxyl-propyl β-CD, sulfobutyl ether β-CD, and others.
Poly(Ethylene Glycol) and Monomethoxy Poly(Ethylene Glycol)
Poly(ethylene glycol) (PEG) is a biocompatible and biodegradable linear polymer with the ethylene glycol repeat unit, —(OCH2CH2)n—. The general structure of PEG is H—(OCH2CH2)n—OH. Monomethoxy poly(ethylene glycol) (MPEG) is a derivative of PEG with the formula CH3—(OCH2CH2)n—OH, in which one functional —OH group is at one end of the chain and the —OH group at the other end replaced by the inert —OCH3 group. MPEG is used for the preparation of bio-conjugates when an inert group is desired at an exposed end of the PEG chain to prevent cross-linking by two —OH functional groups in one PEG chain.
PEG in general is highly water soluble and also soluble in many organic solvents including dichloromethane (DCM), dimethyl sulfoxide (DMSO), chloroform, etc. Studies have revealed that each ethylene glycol subunit is associated with two to three water molecules arising from the hydrophilic nature of the polymer. PEGs and chemically modified PEGs are widely used in the fields of biology, chemistry, biomedicine and pharmacology. The beneficial properties of PEGs and their derivatives arise from their nontoxicity, non-immunogenicity, biocompatibility, biodegradability and high water solubility. PEGs have been approved by the U.S. Food and Drug Administration for internal and topical usages.
So far, PEGs have been used as covalent modifiers of a variety of substrates to produce conjugates whose properties combine the properties of PEG and the starting substrates. Studies have shown that PEG coatings on the surfaces of biological nanoparticles can enhance their water solubility, reduce renal clearance, improve controlled drug-release, provide longevity in the blood stream and ease toxicity of biomedical materials. It was also found that if coated with a low molecular weight PEG, larger particles (e.g., 200 nm and 500 nm in diameter) can decrease mucoadhesion and improve particle penetration through fresh undiluted human mucus. In comparison with their unpegylated counterparts, pegylated drugs are also generally more stable over a range of pH and temperature changes. Hence, PEGs have been widely used to modify the physical and chemical properties of biomedical materials and drugs.
There have been literature reports using PEGs and β-CD derivatives to produce β-CD containing polymers for various purposes.
This “Discussion of the Background” section is provided for background information only. The statements in this “Discussion of the Background” are not an admission that the subject matter disclosed in this “Discussion of the Background” section constitutes prior art to the present disclosure, and no part of this “Discussion of the Background” section may be used as an admission that any part of this application, including this “Discussion of the Background” section, constitutes prior art to the present disclosure.